Current Medicinal Chemistry - Volume 17, Issue 36, 2010

Four different types of small RNAs functionally associated with gene silencing have been discovered in animals including small interfering RNAs (siRNAs), microRNAs (miRNAs), and Piwi-interacting RNAs (piRNAs). Experimental evidence suggests that miRNAs regulate the expression of more than 30% of protein-coding genes. These molecules can also act as oncogenes or tumor suppressors. Expression profiling has revealed characteristic miRNA signatures not only in human cancers but also in serum and blood cells of cancer patients. Numerous human miRNA genes map to chromosomal regions which are susceptible to amplification, deletion or translocation in the process of tumor development. Despite the pivotal role of miRNA in cancer precise mechanisms of action are yet to be elucidated. This review is focused on recent findings related to the emerging field of miRNA serving as novel potential biomarkers in cancer diagnosis, prognosis and possibly, therapies.

Phisiological activation of PI3K pathway is necessary for cells to regulate many different physiological processes such as transcription, protein synthesis, metabolic responses and membrane trafficking. Abnormal activation of the PI3K pathway leads to an increased activity resulting in tumor onset, maintenance, progression and invasion. Both genetic and epigenetic alterations could affect the normal pathway's activation. Ovarian cancer is the leading cause of death from gynaecological malignancies in the western world. PI3K pathway has been recorded as one of the most deregulated signalling pathway in many tumors, including ovarian ones. So it could be considered an attractive target to be investigated with the various classes of chemical compounds already present or in development. In this rewiew we'll try to discuss the published data of the inhibitors targeting members of the PI3K/ akt/ mTOR pathway in the ovarian cancer setting from a preclinical and clinical point of view, with particular emphasis on drugs combination and strategies of administration. Relevant issues and limitations to the use of particular compounds will be also addressed.

Matrix metalloproteinases (MMPs) comprise a large family of zinc-dependent endopeptidases, which are best known for their ability to degrade essentially all components of the extracellular matrix (ECM). By breaking down ECM, MMPs may remove physical barriers, thus allowing cells to migrate and potentially invade other tissues. Recent evidence, however, shows that the proteolytic activities of MMPs also affect several fundamental physiological processes. Primary human acute myeloid leukemia (AML) cells often show constitutive release of several MMPs and chemokines, and there seems to be a crosstalk between the MMP system and the chemokine network. Firstly, the nuclear factor-κB (NF-κB) system represents a common regulator at the transcriptional level both for MMPs (e.g. MMP-1 and MMP-9) and for the constitutive release of several chemokines (CCL2-4/CXCL1/8) by primary human AML cells. Secondly, the crosstalk at the molecular level probably includes MMP-mediated structural alteration and activation of constitutively released chemokines involved in AML cell migration (e.g. CXCL12) and stimulation of bone marrow angiogenesis (e.g. CXCL8). Thirdly, at a functional level the two systems interact because the chemokine network plays a role in similar physiological processes as the MMPs, including AML cell proliferation and migration and local regulation of angiogenesis. Both the chemokine system and MMPs are currently being evaluated as targets in anti-angiogenesis/cancer therapy and may also have potential therapeutic implications in AML. This review introduces the different members of the MMP family and describes their interactions with the chemokine network and the possible involvement of MMPs together with chemokines in leukemogenesis and chemosensitivity in AML.

It is commonly accepted that melatonin (N-acetyl-5-methoxytryptamine), the most relevant pineal secretory product, has oncostatic properties in a wide variety of tumors and, especially, in those identified as being hormone-dependent. The objective of the present article is to offer a global and integrative view of the mechanisms involved in the oncostatic actions of this indoleamine. Due to the wide spectrum of melatonin's actions, the mechanisms that may be involved in its ability to counteract tumor growth are varied. These include: a) antioxidant effects; b) regulation of the estrogen receptor expression and transactivation; c) modulation of the enzymes involved in the local synthesis of estrogens; d) modulation of cell cycle and induction of apoptosis; e) inhibition of telomerase activity; f) inhibition of metastasis; g) prevention of circadian disruption; h) antiangiogenesis; i) epigenetic effects; j) stimulation of cell differentiation; and k) activation of the immune system. The data supporting each of these oncostatic actions of melatonin are summarized in this review. Moreover, the list of actions described may not be exhaustive in terms of how melatonin modulates tumor growth.

The field of drug delivery is advancing rapidly. By controlling the precise level and/or location of a given drug in the body, side effects are reduced, doses are lowered, and new therapies are possible. Nonetheless, substantial challenges remain for delivering specific drugs into specific cells. Computational methods to predict the binding and dynamics between drug molecule and its carrier are increasingly desirable to minimize the investment in drug design and development. Significant progress in computational simulation is making it possible to understand the mechanism of drug delivery. This review summarizes the computational methods and progress of four categories of drug delivery systems: dendrimers, polymer micelle, liposome and carbon nanotubes. Computational simulations are particularly valuable in designing better drug carriers and addressing issues that are difficult to be explored by laboratory experiments, such as diffusion, dynamics, etc.

Spinal cord injury (SCI) damages axons and disrupts myelination interrupting sensory and motor neuronal transmission to and from the brain. Patients suffering from SCI although continue to survive, are often left chronically disabled and with no promise of a cure. Advances in stem cell biology has opened up doors for the use of human embryonic, adult neural and induced pluripotent stem cell strategies for SCI. Despite great promise from animal research, clinical trials have been limited and the jury is still out on its safety and efficacy. This review discusses the advantages and disadvantages of the various stem cell types, barriers hindering translation from animal to humans, and the need for established guidelines for standardization of clinical trials ensuring subsequent implementation. Ultimately, unrealistic expectations of stem cell therapy (SCT) as the elixir for SCI should be managed. The success of SCT for SCI lies in the network of research scientists, medical professionals and patients working cooperatively to build up a knowledge-intensive platform for a comprehensive risk-benefit assessment of SCT for SCI.

The development of atherosclerotic lesions leading to myocardial infarction (MI) or stroke encompasses a cascade of cellular and molecular events that can well be characterized as a chronic immune-mediated inflammation occurring preferentially in the biologic surrounding of the so called metabolic syndrome. Adipokines, chemokines, cytokines, and their receptors are critically involved in the initiation and perpetuation of atherosclerosis, and they play important roles at all levels in the pathogenesis of this disease. Metabolic risk profiles associated with sedentary lifestyle, obesity, especially intra-abdominal fat accumulation, insulin resistance, and dyslipidemia pave the way for a chronic, immunemediated vascular inflammation around vascular lipid deposits. In the present article, the impact of adiponectin, monocyte and T-cell associated cytokines (with emphasis on Neopterin), individual adipose tissue - distribution, and pleiotropic drug effects on the individual course of atherosclerosis and associated cardiovascular disease are reviewed.

Traditional Chinese medicine (TCM) has undergone a long history of clinical practice, which can arrive at ideal therapeutic effects by regulating the body's overall function. However, the complex nature of TCM determines a difficult study on the mechanism and material base of TCM. The current investigations of TCM indicate that the development of modern biotechnology will offer a strong arm in the process of the study. This review focused on the application of the modern biotechnology, including transgenic, gene knockout, cell membrane chromatography (CMC), molecular biochromatography (MBC), gene chips, proteomics, etc. in the research of pharmacodynamic effects of TCM at levels of whole animal, cell and molecular models over the past decade. The whole animal models established by the transgenic and gene knockout technology can truly reflect the characteristics of the target gene activity. Thereby the created animal model could share the pathology of maximum degree of approximation. Cellular models are especially suitable for the situation that functional proteins, enzymes, or drug targets are difficult to separate, or the characteristics of the drugs are unidentified. The utilization of MBC can not only achieve high-throughput screening, but also directly detect the chemical composition of the active components relative to the receptors. Based on the remarkable progress of genomics and proteomics and the technique of gene chips, the bioactive components of TCM can be screened through observing the changes of genes or proteins before and after the compounds acting on the cells.

The development of neuroactive drugs is a time consuming procedure. Candidate drugs must be run through a battery of tests, including receptor studies and behavioural tests on animals. As a rule, numerous substances with promising properties as assessed in receptor studies must be eliminated from the development pipeline in advanced test phases because of unforeseen problems like intolerable side-effects or unsatisfactory performance in the whole organism. Clearly, test systems of intermediate complexity would alleviate this inefficiency. In this review, we propose cultured organotypic brain slices as model systems that could bridge the ‘interpolation gap’ between receptors and the brain, with a focus on the development of new general anaesthetics with lesser side effects. General anaesthesia is based on the modulation of neurotransmitter receptors and other conductances located on neurons in diverse brain regions, including cerebral cortex and spinal cord. It is well known that different components of general anaesthesia, e.g. hypnosis and immobility, are produced by the depression of neuronal activity in distinct brain regions. The ventral horn of the spinal cord is an important structure for the induction of immobility. Thus, the potentially immobilizing effects of a newly designed drug can be estimated from its depressant effect on neuronal network activity in cultured spinal slices. A drug's sedative and hypnotic potential can be examined in cortical cultures. Combined with genetically engineered mice, this approach can point to receptor subtypes most relevant to the drug's intended net effect and in return can help in the design of more selective drugs. In conclusion, the use of organotypic cultures permits predictions of neuroactive properties of newly designed drugs on an intermediate level, and should therefore open up avenues for a more creative and economic drug development process.

Since the discovery of the Jak2-V617F mutation as the causative agent in a large number of myeloproliferative neoplasms (MPNs), there has been a drive to develop Jak2 specific inhibitors that can be used in therapy for MPN patients and other Jak2-related pathologies. Over the past few years, a number of research groups have sought to develop Jak2 tyrosine kinase inhibitors. These compounds are currently in pre-clinical or clinical trials. Unfortunately, there is still a need for more potent, specific, and orally bioavailable drugs to treat these diseases. Within the past twelve months, a variety of medicinal chemistry techniques have produced several lead compounds that exhibit promising Jak2 inhibitory properties. The majority of these inhibitors target the Jak2 kinase domain in general and the ATP-binding pocket in particular. In this review, we summarize these studies and discuss the structure activity relationship (SAR) properties of several compounds. As we learn more about the key structural components that provide potency and specificity in Jak2 inhibition, we will come closer to finding suitable treatment options for individuals suffering from Jak2-mediated pathologies.

Rapid innovations in nanomedicine have increased the likelihood that engineered nanomaterials will eventually come in contact with humans and the environment. The advent of nanotechnology has created strong interest in many fields such as biomedical sciences and engineering field. Central to any significant advances in nanomaterial based applications will be the development of functionalized nanoparticles, which are believed to hold promise for use in fields such as pharmaceutical and biomedical sciences. Early clinical results have suggested that functionalization of nanoparticles with specific recognition chemical moieties indeed yields multifunctional nanoparticles with enhanced efficacy, while simultaneously reducing side effects, due to properties such as targeted localization in tumors and active cellular uptake. A prerequisite for advancing this area of research is the development of chemical methods to conjugate chemical moieties onto nanoparticles in a reliable manner. In recent years a variety of chemical methods have been developed to synthesize functionalized nanoparticles specifically for drug delivery, cancer therapy, diagnostics, tissue engineering and molecular biology, and the structure-function relationship of these functionalized nanoparticles has been extensively examined. With the growing understanding of methods to functionalize nanoparticles and the continued efforts of creative scientists to advance this technology, it is likely that functionalized nanoparticles will become an important tool in the above mentioned areas. Therefore, the aim of this review is to provide basic information on nanoparticles, describe previously developed methods to functionalize nanoparticles and discuss their potential applications in biomedical sciences. The information provided in this review is important in regards to the safe and widespread use of functionalized nanoparticles particularly in the biomedicine field.

Platelets play a central role in the pathogenesis of the atherothrombosis which ultimately causes myocardial infarction, stroke and peripheral vascular disease. Commonly used oral anti-platelet drugs include aspirin (an irreversible inhibitor of cyclo-oxygenase), clopidogrel (an ADP receptor antagonist), other thienopyridines such as ticlopidine and prasgruel, and dipyridamole (an inhibitor of adenosine reuptake and platelet phosphodiesterase). Newer agents are in development and one, ticagrelor, a reversible ADP receptor antagonist has shown promise. Despite their proven benefit, recurrent vascular events still occur in those taking anti-platelet drugs. This has led to the concept of anti-platelet resistance, most commonly aspirin resistance as this drug is the cornerstone of most regimens. The causes of aspirin resistance are numerous but potential mechanisms include lack of patient adherence, non COX-1 mediated thromboxane A2 synthesis, increased activity of alternate platelet activation pathways, interference of aspirin action by other drugs and probably pharmacogenetic factors. Measurement of platelet response to aspirin is made possible using a number of in-vitro laboratory assays of platelet function which include measurement of thromboxane A2 metabolites as well as newer point-of-care assays of platelet aggregation. The phenomenon of aspirin resistance is important as it raises the possibility of developing strategies to identify those who respond best to a particular anti-platelet regimen, or to development of newer anti-platelet therapies to which more patients respond. This review discusses important aspects of aspirin resistance both in terms of clinical medicine, alternative anti-platelet strategies, and the potential to overcome its various causes.

Obesity is the effect of imbalance between energy intake and expenditure and forms a fundamental basis of the metabolic syndrome. A number of substances implicated in the regulation of energy metabolism represent opportunities for anti-obesity drug development. Neuronal histamine and its receptors have been shown to regulate energy metabolism and are considered as anti-obesity targets. Several histamine receptor subtypes have been identified; of these, histamine H1 and H3 receptors (H1-R and H3-R) have been specifically recognized as mediators of energy intake and expenditure. In addition, several histamine drugs related to H1-R and H3-R, have been shown to attenuate body weight gain both in rodent and human. These results provide the reagents for histamine receptors biology and may find applications in the treatment of obesity and related metabolic disorders. In this review, the development of agonists and antagonists of histamine receptors are provided.